US4985428A - Isoxazoles with nootropic activity - Google Patents
Isoxazoles with nootropic activity Download PDFInfo
- Publication number
- US4985428A US4985428A US07/302,747 US30274789A US4985428A US 4985428 A US4985428 A US 4985428A US 30274789 A US30274789 A US 30274789A US 4985428 A US4985428 A US 4985428A
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- US
- United States
- Prior art keywords
- compound
- group
- formula
- hydroxy
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to compounds with nootropic activity and, more particularly, it relates to derivatives of N-(5-isox-azolecarbonyl)-4-aminobutyric acid, the processes for their preparation, their therapeutic use and the pharmaceutical compositions containing them as active ingredient.
- Piracetam, 2-pyrrolidinoneacetamide (Merck Index, X edition, page 1080, no. 7363) is a compound described in Belgian Pat. No. 667906 (Union Chimique Belge) as central stimulant.
- Piracetam For its action at cerebral level on glucose metabolism as well as, especially, in increasing acetylcholine release, Piracetam is considered the parent compound of nootropic drugs and it is used in therapy in the treatment of cerebral efficiency disorders, particularly in elderly patients.
- Piracetam even if it is used in therapy, shows a relative effectiveness.
- n a number selected from 1 and 2;
- R represents a hydrogen atom, a halogen atom, hydroxy, a C 1 -C 6 alkyl or alkoxy;
- R 1 represents hydroxy, an optionally unsaturated C 1 -C 18 alkoxy or an ##STR2## group
- R 2 and R 3 represent a hydrogen atom, a linear or branched C 1 -C 6 alkyl, a group of formula (CH 2 ) m R 4 wherein
- n represents an integer selected from 1, 2 ,and 3;
- R 4 represents a carboxy group, an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxy moiety or a group of formula ##STR3##
- R 5 and R 6 represent a hydrogen atom or a linear or branched C 1 -C 6 alkyl
- R 2 and R 3 represents a group of formula ##STR4## wherein R 4 has the above reported meanings and R 7 represents a linear or branched C 1 -C 4 alkyl optionally substituted by phenyl, hydroxy or by a mercapto group; and the other represents a hydrogen atom;
- R 2 and R 3 together with the nitrogen atom to which they are bonded, form a 5, 6 or 7 membered heterocycle which may further contain 1 or 2 heteroatoms selected among nitrogen, oxygen and sulphur.
- a further object of the present invention are the salts of the compounds of formula I, which have an acidic function, with pharmaceutically acceptable organic or inorganic bases and the salts of the compounds of formula I, wherein R 1 contains a basic function, with organic or inorganic acids suitable for pharmaceutical use.
- organic or inorganic bases useful as salifying agents are sodium or potassium hydroxides, ammonium hydroxide, lysine, arginine, cysteine and 2-amino-2-hydroxymethyl-1,3-propanediol.
- organic or inorganic acids useful as salifying agents are hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, citric acid and glutamic acid.
- the compounds of formula I, object of the present invention have nootropic activity.
- Examples of compounds comprised in formula I are the following: ##STR5## wherein R has the above reported meanings but preferably it represents a chlorine or bromine atom, hydroxy, methoxy or ethoxy, methyl or ethyl.
- the preparation of the compounds of formula I is another object of the present invention and comprises a condensation reaction between a chloride of 5-isoxazolecarboxylic acid of formula ##STR6## wherein
- R has the above reported meanings, and 4-aminobutyric acid or a derivative thereof of formula
- n and R 1 have the above reported meanings, in an inert solvent in the presence of an acceptor of halogenhydric acids.
- acceptors of halogenhydric acids are inorganic or organic bases such as sodium hydroxide or carbonate, triethylamine, N-methyl-morpholine and pyridine.
- the esterification reaction is carried out with saturated or unsaturated aliphatic alcohols such as methanol, ethanol, propanol, butanol, cetylic alcohol, linolenic alcohol or stearic alcohol, in the presence of catalytic amounts of an inorganic acid.
- saturated or unsaturated aliphatic alcohols such as methanol, ethanol, propanol, butanol, cetylic alcohol, linolenic alcohol or stearic alcohol
- Examples of reactive derivatives (III) of the compounds of formula Ia are mixed anhydrides obtainable by reaction with alkylchloroformates such as isobutylchloroformate.
- suitable amino derivatives of formula IV are ammonia, mono- or di-substituted amines such as methylamine, dimethylamine, diethylamine and di-n.propylamine; alkylendiamines such as N,N-diethyl-ethylendiamine and N,N-diisopropyl-ethylendiamine; cyclic derivatives such as pyrrolidine, 2-pyrrolidinone, piperazine and N-methyl-piperazine or natural aminoacids such as glycine, alanine, valine, serine, cysteine, phenylalanine and derivatives thereof.
- the cyclization reaction is carried out in one step through the formation of the corresponding acyl halide as intermediate.
- the intermediate acyl halides are prepared by reaction with a suitable halogenating agents such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentachloride, oxalyl bromide and oxalyl chloride.
- a suitable halogenating agents such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentachloride, oxalyl bromide and oxalyl chloride.
- thionyl chloride is preferably used.
- esterification of the carboxyl group can be carried out directly on 4-aminobutyric acid or a derivative thereof, that is before condensation with compound II.
- the compounds of formula I are active on central nervous system and they can be used in pharmaceutical field as nootropics.
- ECS electroshock
- the ED 50 values are up to 20 times lower in case of "per os" administration and up to 10 times lower by perfusion than that of Piracetam.
- the compounds of formula I have no toxicological problem. They exhibit a complete tolerability even when they are administered by perfusion at dose of 2 g/kg.
- the therapeutic uses of the compounds object of the present invention are in the treatment of impairments of cerebral functionality due to ageing as well as to pathologic or traumatic reasons such as for example amnesia and decrease in cognitive capacity.
- the therapeutic dose of the compounds of formula I and of the salts thereof depends on several factors such as the way of administration, the specific pharmaceutical composition, the treatment needed and the individual response to the therapy. In general it will be comprised between 5 and 2000 mg/day in one or more administrations.
- a further object of the present invention are the pharmaceutical compositions containing the compounds of formula I or pharmaceutically acceptable salts thereof as active ingredient optionally together with one or more, solid or liquid, organic or inorganic pharmaceutical excipients such as diluents, preserving agents, moistening agents, colouring agents, flavouring agents and so on.
- the pharmaceutical compositions object of the present invention can be administered in solid pharmaceutical preparations, such as tablets, coated tablets, capsules, granulates and suppositories or in liquid pharmaceutical preparations such as syrups, suspensions, emulsions and solutions suitable for oral or parenteral administration.
- the compounds object of the present invention can be prepared in slow and protracted release pharmaceutical formulations too.
- the pharmaceutical compositions object of the present invention may also contain the compounds of formula I or pharmaceutically acceptable salts thereof in association with other active ingredients selected, for example, among aminoacids, N-acetyl-cysteine, co-enzymes, mineral salts and vitamins.
- compositions object of the present invention is carried out by usual techniques.
- the precipitate was extracted three times with ethyl acetate (200 ml). The organic extracts were collected, washed with water and dried on sodium sulphate.
- N-(3-bromo-5-isoxazolecarbonyl)-4-aminobutyric acid (11.8 g; 0.04 mol), prepared according to the method described in example 1, and N-methyl-morpholine (4.41 ml; 0.04 mol) in anhydrous tetrahydrofuran (260 ml), cooled at -15° C., isobutylchloroformate (5.22 ml; 0.04 mol) was slowly added.
- reaction mixture was kept under stirring for 6 hours at room temperature and then it was extracted with HCl 0.1N (20 ml), with water, with a saturated aqueous solution of NaHCO 3 (20 ml) and finally with water up to neutral pH.
- the organic layer was dried on sodium sulphate and, after evaporation of the solvent, the solid residue was crystallized from diisopropylether.
- the solution was diluted with water (200 ml) and extracted twice with chloroform (50 ml).
- the aqueous layer was acidified to pH 2 with HCl at 10%.
- the precipitate was filtered, washed with water up to neutral pH and it was crystallized from isopropanol (200 ml).
- N-[N-(3-bromo-5-isoxazolecarbonyl)-4-aminobutyroyl]-4-aminobutyric acid was obtained (20.8 g; 94% yield) with m.p. 157°-158° C.
- N-(3-bromo-5-isoxazolecarbonyl)-4-aminobutyric acid (69.27 g; 0.25 mol), prepared according to the method described in example 1, and triethylamine (34.80 ml; 0.25 mol) in anhydrous tetrahydrofuran (700 ml), cooled at --15° C., isobutylchloroformate (32.67 ml; 0.25 mol) was added slowly.
- N-[N-(3-bromo-5-isoxazolecarbonyl)-4-aminobutyroyl]-4-aminobutyric acid was obtained (55.5 g; 61% yield) with m.p. 157°-158° C.
- ECS electroshock
- the test consisted in two experiments with a resting interval of 24 hours between them.
- the animals were trained to associate the passage from a light partition to a dark one, in a suitable box, with a noxious stimulation that is an electric stimulation through an electrified grid (foot-shock: 1 mA for 10 seconds).
- a first group of rats (hereinafter indicated as control), which remembered the association between the passage and the noxious stimulation, showed a conditioned response that led to avoid the repetition of the passage.
- ECS control A second group of animals (hereinafter indicated as ECS control), which underwent a treatment for inducing amnesia (ECS: 90 mA, 100 Hz for 1 second) immediately after the training session, showed a decreased conditioned response and a large number of rats repeated the passage.
- the average time (retention time) utilized for the passage was 54 seconds for the control and 32 seconds for the ECS control.
- Groups of 20 rats underwent the training session, the treatment for inducing amnesia and the retention session after administration of the compounds object of the present invention and of the reference compounds, Piracetam and Aniracetam.
- the administration was carried out 30 minutes before the training session in case of intraperitoneal administration (i.p.) and 60 minutes before in case of administration by oral route. At least three doses each compound and each administration route were tested.
- the difference between the retention time of the control and the retention time of the ECS control was considered as reference ( ⁇ t) and it was fixed, as percentage, equal to 100.
- ED 50 that is as the dose of compound able to give an improvement of the retention time equal to 50% of the reference interval ( ⁇ t) in comparison with the ECS control.
- ED 50 values of some representatives of the compounds of formula I are reported in table 1.
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hospice & Palliative Care (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Psychiatry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT20590/87A IT1205015B (it) | 1987-05-20 | 1987-05-20 | Composti ad attivita' nootropa |
IT20589A/87 | 1987-05-20 | ||
IT20589/87A IT1205014B (it) | 1987-05-20 | 1987-05-20 | Composti ad attivita' nootropa |
IT20590A/87 | 1987-05-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
US4985428A true US4985428A (en) | 1991-01-15 |
Family
ID=26327590
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US07/302,747 Expired - Lifetime US4985428A (en) | 1987-05-20 | 1988-05-19 | Isoxazoles with nootropic activity |
Country Status (10)
Country | Link |
---|---|
US (1) | US4985428A (ja) |
EP (1) | EP0317588B1 (ja) |
JP (1) | JPH02500365A (ja) |
AT (1) | ATE65997T1 (ja) |
AU (1) | AU599809B2 (ja) |
DE (1) | DE3864124D1 (ja) |
DK (1) | DK4389A (ja) |
FI (1) | FI89266C (ja) |
NO (1) | NO172120C (ja) |
WO (1) | WO1988009330A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5273989A (en) * | 1990-04-12 | 1993-12-28 | Hoechst Aktiengesellschaft | 3,5-disubstituted 2-isoxazolines and isoxazoles, agents containing them and their use |
US20050101539A1 (en) * | 2001-02-05 | 2005-05-12 | Jean Rapin | Tripeptide derivatives for the treatment of postlesional diseases of the nervous system |
US20080108679A1 (en) * | 2004-11-16 | 2008-05-08 | Zambon S.P.A. | Isoxazolic Derivative to Relieve Neuropathic Pain |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3459738A (en) * | 1964-08-06 | 1969-08-05 | Ucb Sa | N-substituted lactams |
US4833140A (en) * | 1983-10-04 | 1989-05-23 | Boehringer Ingelheim Kg | 1-(benzyl or pyridylmethyl)-4 or 5-aminomethyl-pyrrolidin-2-ones |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2024M (fr) * | 1961-02-01 | 1963-09-23 | Shionogi & Co | Utilisation de dérivés de l'isoxazole pour le traitement des maladies mentales et particulierement des dépressions nerveuses. |
-
1988
- 1988-05-19 DE DE8888904406T patent/DE3864124D1/de not_active Expired - Lifetime
- 1988-05-19 AT AT88904406T patent/ATE65997T1/de active
- 1988-05-19 EP EP88904406A patent/EP0317588B1/en not_active Expired - Lifetime
- 1988-05-19 US US07/302,747 patent/US4985428A/en not_active Expired - Lifetime
- 1988-05-19 JP JP63504091A patent/JPH02500365A/ja active Pending
- 1988-05-19 WO PCT/EP1988/000445 patent/WO1988009330A1/en active IP Right Grant
- 1988-05-19 AU AU17869/88A patent/AU599809B2/en not_active Ceased
-
1989
- 1989-01-06 DK DK004389A patent/DK4389A/da not_active Application Discontinuation
- 1989-01-13 FI FI890173A patent/FI89266C/fi not_active IP Right Cessation
- 1989-01-19 NO NO890245A patent/NO172120C/no unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3459738A (en) * | 1964-08-06 | 1969-08-05 | Ucb Sa | N-substituted lactams |
US4833140A (en) * | 1983-10-04 | 1989-05-23 | Boehringer Ingelheim Kg | 1-(benzyl or pyridylmethyl)-4 or 5-aminomethyl-pyrrolidin-2-ones |
Non-Patent Citations (5)
Title |
---|
Branconnier et al., Psychopharmacology Bulletin, 19, p. 726. * |
Hano et al., Chemical Abstracts, vol. 72, No. 132705 (1970). * |
Moos et al., Medicinal Research Reviews, 8, pp. 353 391 (1988). * |
Moos et al., Medicinal Research Reviews, 8, pp. 353-391 (1988). |
Zeeh et al., Chemical Abstracts, vol. 95, No. 62168 (1981). * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5273989A (en) * | 1990-04-12 | 1993-12-28 | Hoechst Aktiengesellschaft | 3,5-disubstituted 2-isoxazolines and isoxazoles, agents containing them and their use |
US20050101539A1 (en) * | 2001-02-05 | 2005-05-12 | Jean Rapin | Tripeptide derivatives for the treatment of postlesional diseases of the nervous system |
US7163922B2 (en) * | 2001-02-05 | 2007-01-16 | Neurotell Ag | Tripeptide derivatives for the treatment of postlesional diseases of the nervous system |
US20080108679A1 (en) * | 2004-11-16 | 2008-05-08 | Zambon S.P.A. | Isoxazolic Derivative to Relieve Neuropathic Pain |
US7834040B2 (en) * | 2004-11-16 | 2010-11-16 | Zambon S.P.A. | Isoxazolic derivative to relieve neuropathic pain |
Also Published As
Publication number | Publication date |
---|---|
EP0317588B1 (en) | 1991-08-07 |
NO172120B (no) | 1993-03-01 |
FI89266B (fi) | 1993-05-31 |
JPH02500365A (ja) | 1990-02-08 |
FI89266C (fi) | 1993-09-10 |
NO890245L (no) | 1989-01-19 |
ATE65997T1 (de) | 1991-08-15 |
NO172120C (no) | 1993-06-09 |
DK4389D0 (da) | 1989-01-06 |
DE3864124D1 (de) | 1991-09-12 |
DK4389A (da) | 1989-01-06 |
EP0317588A1 (en) | 1989-05-31 |
WO1988009330A1 (en) | 1988-12-01 |
FI890173A0 (fi) | 1989-01-13 |
FI890173A (fi) | 1989-01-13 |
AU1786988A (en) | 1988-12-21 |
AU599809B2 (en) | 1990-07-26 |
NO890245D0 (no) | 1989-01-19 |
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Owner name: ZAMBON GROUP S.P.A., ITALY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:CARENZI, ANGELO;CHIARINO, DARIO;DELLA BELLA, DAVIDE;AND OTHERS;REEL/FRAME:005437/0209;SIGNING DATES FROM 19890111 TO 19890113 |
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Free format text: PATENTED CASE |
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